The real estate mogul tweeted that the Texas senator should "be careful" or he would "spill the beans on your wife" Heidi Cruz.
"Lyin' Ted Cruz just used a picture of Melania from a G.Q. shoot in his ad. Be careful, Lyin' Ted, or I will spill the beans on your wife!," he tweeted Tuesday evening, just minutes before polls closed in Arizona. Trump tweeted and deleted a similar version of the Tweet about 10 minutes earlier.
Trump appears to be referring to a Facebook advertisement targeted to Mormons that shows Trump's wife, Melania, posing nude. That ad was produced by an anti-Trump super PAC, Make America Awesome, which has no known connection to the Cruz campaign.
Cruz responded on Twitter by saying that the ad was not from him and if he went after his wife, then Trump is a "coward."
"Pic of your wife not from us. Donald, if you try to attack Heidi, you're more of a coward than I thought. #classless," Cruz tweeted
Trump retweeted a follower early Thursday morning who posted a picture of Heidi Cruz alongside a glamor shot of Melania Trump. The caption reads: "no need to 'spill the beans' the images are worth a thousand words."
Cruz responded by retweeting Trump and adding "Donald, real men don't attack women. Your wife is lovely, and Heidi is the love of my life."
Heidi Cruz is a senior executive for Goldman Sachs, and took a leave from work in order to help her husband's campaign. She has become one of the campaign's most accomplished fundraisers.
The senator's wife hit back at Trump on the campaign trail in Wisconsin.
"Well, as you probably know by now, most of the things, many of the things others say are not based in reality," Heidi Cruz said.
"I have one job on this campaign, and it is to be helping Ted win this race. And it is, I think, the easiest job in the world, and that is to speak the truth: what I know about my husband, our family, myself," she added.
Heidi Cruz also denied the photo of Melania Trump came from the Cruz campaign.
"In no shape or form are we related to it," she said.
Trump again accused the Cruz campaign of being behind the ad on Wednesday, tweeting, "Lyin' Ted Cruz denied that he had anything to do with the G.Q. model photo post of Melania. That's why we call him Lyin' Ted!"
The Trump campaign did not immediately respond to a request for comment.
John Kasich, the third Republican candidate in the race, weighed in from the trail Wednesday that he "wouldn't go there" in terms of personal attacks.
"These sort of personal things are way out of bounds," Kasich said from Wauwatosa, Wisconsin.
Trump previously has used Twitter to threaten the Ricketts family, which has financed a negative ad campaign against him.